DESCRIPTION: The research is designed to characterize the mechanism(s) of hypertension in a unique genetic canine model of hypertension, the Pennsylvania Hypertensive Dog (PHD). The goal of this revised competitive renewal pplication is to continue studies of the natural history, physiology, and genetics in this large animal model of essential hypertension. Studies will be conducted to assess the long- term effect of hypertension on renal function and structure of the peripheral vasculature: Dr. Bovee's laboratory at Penn will define the pattern of inheritance (leading to eventual DNA analyses): 1. by continued line-breeding in collaboration with a commercial breeder; 2. start an outbreeding program with Butler Farms; 3. continue longitudinal studies of effect of hypertension and aging on hematology and pathology; 4. estimate sympathetic nerve activity to the systemic circulation and to the kidneys by measuring norepinephrine spillover. Losartan will be given to some animals to test whether angiotensin II increases norepinephrine release from sympathetic nerves; and 5. evaluate vascular sensitivity to exogenous adrenergic agents such as norepinephrine and angiotensin in conscious dogs on different salt diets. Studies conducted during the previous funding period reveals that the PHD dogs are not sodium sensitive and that the hypertension is not dependent on the renin-angiotensin system (RAS). Accordingly, the focus has changed to neurogenic origin of hypertension. The new working hypothesis is that abnormal renal nerve activity elevates arterial pressure.